Glutamate Dehydrogenase 1 Signals through Antioxidant Glutathione Peroxidase 1 to Regulate Redox Homeostasis and Tumor Growth

Lingtao Jin, Dan Li, Gina N. Alesi, Jun Fan, Hee Bum Kang, Zhou Lu, Titus J. Boggon, Peng Jin, Hong Yi, Elizabeth R. Wright, Duc Duong, Nicholas T. Seyfried, Robert Egnatchik, Ralph J. DeBerardinis, Kelly R. Magliocca, Chuan He, Martha L. Arellano, J. Hanna J Khoury, Dong M. Shin, Fadlo R. KhuriSumin Kang

Research output: Contribution to journalArticle

117 Scopus citations

Abstract

How mitochondrial glutaminolysis contributes to redox homeostasis in cancer cells remains unclear. Here we report that the mitochondrial enzyme glutamate dehydrogenase 1 (GDH1) is commonly upregulated in human cancers. GDH1 is important for redox homeostasis in cancer cells by controlling the intracellular levels of its product alpha-ketoglutarate and subsequent metabolite fumarate. Mechanistically, fumarate binds to and activates a reactive oxygen species scavenging enzyme glutathione peroxidase 1. Targeting GDH1 by shRNA or a small molecule inhibitor R162 resulted in imbalanced redox homeostasis, leading to attenuated cancer cell proliferation and tumor growth.

Original languageEnglish (US)
Pages (from-to)257-270
Number of pages14
JournalCancer Cell
Volume27
Issue number2
DOIs
StatePublished - Feb 9 2015

ASJC Scopus subject areas

  • Oncology
  • Cell Biology
  • Cancer Research

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    Jin, L., Li, D., Alesi, G. N., Fan, J., Kang, H. B., Lu, Z., Boggon, T. J., Jin, P., Yi, H., Wright, E. R., Duong, D., Seyfried, N. T., Egnatchik, R., DeBerardinis, R. J., Magliocca, K. R., He, C., Arellano, M. L., Khoury, J. H. J., Shin, D. M., ... Kang, S. (2015). Glutamate Dehydrogenase 1 Signals through Antioxidant Glutathione Peroxidase 1 to Regulate Redox Homeostasis and Tumor Growth. Cancer Cell, 27(2), 257-270. https://doi.org/10.1016/j.ccell.2014.12.006